Definition of the biochemical effects of antineoplastic drugs on mammalian cells, and of the relation between those effects and cell-killing activity, is required for a rational approach to drug development. This information would be especially useful now for the chloroethyl nitrosoureas, because it would provide a basis for selection of candidate compounds for clinical trial among the many compounds currently available, and could guide the synthesis of new and more effective compounds. Chloroethyl nitrosoureas decompose quickly. One decomposition product is a chloroethyl carbonium ion - an alkylating agent, which is believed to be responsible for DNA cross-linking. The other principal product of decomposition is an isocyanate; the structure of the isocyanate, as well as its carbamoylating ability, varies from one nitrosourea to the next. Strong carbamoylating activity is associated with a number of biochemical effects, including inhibition of DNA repair. There is a question whether strong carbamoylating activity is an asset or a liability. This study is aimed at answering that question by comparing several 2-chloroethyl nitrosoureas that have differing amounts of carbamoylating activity. Nitrosoureas will be compared for their effects on DNA structure. The technique of alkaline elution, developed by Kohn and co-workers, will be employed to study: a) formation and removal of cross-links, and b) production and repair of strand breaks. Drug effects on DNA structure will be correlated with cytotoxicity in an attempt to discover which effects may be responsible for cell killing. Nitrosoureas will also be compared for their ability to produce more-than-additive cytotoxicity when given in combination with another DNA-damaging agent -- either a conventional alkylating agent, or x-ray. Synergism already been demonstrated for strongly-carbamoylating nitrosoureas. Whether synergism is dependent upon strong carbamoylating activity is the question.